title: Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3.
abstract: BACKGROUND
  Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na(+)/Ca(2+) exchanger (NCX) has been suggested to work as a trigger for EADs.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP.
  
  
  RESULTS
  In 34 Langendorff-perfused rabbit hearts, the I(Kr)-blocker sotalol (100 microM; n = 18) as well as veratridine (0.5 microM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 microM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups (P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. I(Na) and I(Kr) were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs.
  
  
  CONCLUSIONS
  In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.
authors.affiliation: Department of Cardiology and Angiology, Hospital of the Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Christian
authors.initials: C
authors.lastname: Pott
authors.forename: Martin
authors.initials: M
authors.lastname: Fink
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Denis
authors.initials: D
authors.lastname: Noble
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008133:Long QT Syndrome / Q000145:classification / Q000517:prevention & control*; D032342:Muscle Cells / Q000187:drug effects*; D010647:Phenyl Ethers / Q000494:pharmacology*; D011817:Rabbits; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D016171:Torsades de Pointes / Q000517:prevention & control*
chemical_list: D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger